Previous reports suggest an increased risk of a second cancer, primarily osteosarcoma, in survivors of Ewing's sarcoma. In a retrospective review of 25 long-term irradiated survivors of Ewing's sarcoma, the incidence of second cancers was determined. The patients were free of disease for more than three years (except for one patient who developed a second cancer 2.5 years after diagnosis), with a median follow-up period of 7.6 years. All received megavoltage radiation to the primary tumor. Twenty-four of the 25 patients were treated with chemotherapy. Second cancers developed in two patients. Acute myelogenous leukemia (AML) developed in a seven-year-old 15 months after treatment. An osteosarcoma developed within an irradiated field in a 13-year-old three years after treatment. The actuarial risk of developing a second cancer at five years is 8% whereas the actuarial risk of developing a bone sarcoma is 4%. Genetic factors may play a role in the development of AML in patients with Ewing's sarcoma. Megavoltage radiation, particularly doses greater than 60 Gy, as well as alkylating agent chemotherapy may contribute to the risk for bone sarcoma. The risk of a second cancer after successful treatment of Ewing's sarcoma is similar to that expected for survivors of all childhood cancers.